The Membrane-Microfilament Linker Ezrin Is Involved in the Formation of the Immunological Synapse and in T Cell Activation

Abstract

Dynamic interactions between membrane and cytoskeleton components are crucial for T cell antigen recognition and subsequent cellular activation. We report here that the membrane-microfilament linker ezrin plays an important role in these processes. First, ezrin relocalizes to the contact area between T cells and stimulatory antigen-presenting cells (APCs), accumulating in F-actin-rich membrane protrusions at the periphery of the immunological synapse. Second, T cell receptor (TCR)-mediated intracellular signals are sufficient to induce ezrin relocalization, indicating that this protein is an effector of TCR signaling. Third, overexpression of the membrane binding domain of ezrin perturbs T cell receptor clustering in the T cell-APC contact area and inhibits the activation of nuclear factor for activated T cells (NF-AT).

Germinal center kinases in immune regulation

“…Loss of Ezrin has been correlated with decreased IL-2 production, [102][103][104] as well as with impaired migration of T-cell signaling microclusters consisting of TCR and downstream signaling components. 105 Moreover, ERM proteins also play a role in cAMP-mediated T-cell repression by regulating PKA signaling.…”

CD95/phosphorylated ezrin association underlies HIV-1 GP120/IL-2-induced susceptibility to CD95(APO-1/Fas)-mediated apoptosis of human resting CD4+T lymphocytes

“…On the basis of previous reports, [38][39][40][41][42] we analyzed the capability of HIV-1 gp120-CD4 binding to trigger ezrin Tyrphosphorylation in T lymphocytes (Figure 1c-d). The total cell extracts of PBLs treated with gp120 and/or recombinant IL2 were immunoprecipitated using an anti-ezrin mAb and blotted with an anti P-tyr mAb, in order to test the presence of the Tyrphosphorylated form of ezrin.…”

“…41 Moreover, ezrin binding to membrane proteins is involved both in lymphocyte activation and in the formation of the immunological synapse. 42 Connection to actin is of crucial importance in CD95-mediated apoptosis, both in predisposing T lymphocytes to CD95-mediated apoptosis, 43 and in allowing the early steps of CD95 signaling. 44 Particularly, we have shown that the CD95 polarization, due to the ezrin-mediated CD95/actin association, is the key in rendering human CD4 þ T lymphocytes susceptible to CD95-mediated apoptosis.…”

Ezrin is a negative regulator of death receptor-induced apoptosis

“…How ERM participates in several membrane-associated events in lymphocytes remains unclear. For example, three different roles have been reported for the involvement of ezrin-moesin in immunological synapse (IS) formation: ERM was found to be essential for the assembly of IS and the recruitment of ZAP70 in one group of studies (Roumier et al, 2001;Ilani et al, 2007); ezrin was reported to be completely dispensable for IS formation in another study (Shaffer et al, 2009); and in yet a third proposal, ezrin was also declared to negatively regulate IS formation (Faure et al, 2004). Similarly, opposite effects of ERM have been documented for T-lymphocyte movement; T-cell migration could be enhanced by either ERM phosphorylation (Li et al, 2007) or ERM dephosphorylation (Brown et al, 2003).…”